Suter-Dick, Laura
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Suter-Dick
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Laura
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Suter-Dick, Laura
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- PublikationRat multicellular 3D liver microtissues to explore TGF-β1 induced effects(Elsevier, 13.11.2019) Prestigiacomo, Vincenzo; Weston, Anna; Suter-Dick, Laura [in: Journal of Pharmacological and Toxicological Methods]Chronic liver damage can lead to fibrosis, encompassing hepatocellular injury, activation of Kupffer cells (KC), and activation of hepatic stellate cells (HSC). Inflammation and TGF-β1 are known mediators in the liver fibrosis adverse outcome pathway (AOP). The aim of this project was to develop a suitable rodent cell culture model for the investigation of key events involved in the development of liver fibrosis, specifically the responses to pathophysiological stimuli such as TGF-β1 and LPS-triggered inflammation. We optimized a single step protocol to purify rat primary hepatocytes (Hep), HSC and KC cells to generate 3D co-cultures based on the hanging drop method. This primary multicellular model responded to the profibrotic cytokine TGF-β1 (1 ng/mL) with signs of hepatocellular damage, inflammation and ultimately HSC activation (increase in αSMA expression). LPS elicited an inflammatory response characterized by increased expression of cytokines. 3D-monocultures comprising only Hep displayed different responses, underlying that parenchymal and non-parenchymal cells need to be present in the system to recapitulate fibrosis. The data also suggest that pre-activated HSC may reverse to a quiescent phenotype in 3D, probably due to the more physiological conditions.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationThe role of bile salts in cholestatic injury and fibrosis using a human 3D in vitro model(11/2018) Messner, Catherine; Mauch, Linda; Mannino, Salvatore; Prestigiacomo, Vincenzo; Suter-Dick, Laura06 - Präsentation
- PublikationAssessment of human relevant effects of PTS using relevant in vitro systms(11/2018) Suter-Dick, Laura06 - Präsentation
- PublikationAhR-Mediated Effects of Dioxins on liver in zebrafish embryos(11/2018) Yan, Lu; Zenker, Armin; Suter-Dick, Laura06 - Präsentation
- PublikationMicrofluidic systems and novel biomarkers for the assessment of proximal tubular toxicity(11/2018) Suter-Dick, Laura06 - Präsentation
- Publikation3D human liver microtissues vs. 2D monolayer culture as an in vitro tool for compound testing(10/2018) Messner, Catherine; Prestigiacomo, Vincenzo; Mannino, Salvatore; Mauch, Linda; Suter-Dick, Laura06 - Präsentation
- PublikationTest de toxicidad empleando modelos 3D hechos a medida: Hígado y Riñón(10/2018) Suter-Dick, Laura06 - Präsentation
- PublikationModelling Alzheimer’s disease in three-dimensional human neural progenitor cultures(09/2018) Gaiser, Carine; Weston, Anna; Suter-Dick, Laura06 - Präsentation
- PublikationNephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules(08/2018) Vormann, Marianne K.; Gijzen, Linda; Hutter, Simon; Boot, Lisette; Nicolas, Arnaud; van den Heuvel, Angelique; Vriend, Jelle; Ng, Chee Ping; Nieskens, Tom T.G.; van Duinen, Vincent; de Wagenaar, Bjorn; Masereeuw, Rosalinde; Suter-Dick, Laura; Trietsch, Sebastian J.; Wilmer, Martijn; Joore, Jos; Vulto, Paul; Lanz, Henriette [in: The AAPS Journal]Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.01 - Zeitschriftenartikel, Journalartikel oder Magazin
- PublikationCombining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study(07/2018) Suter-Dick, Laura; Mauch, Linda; Caj, Michaela; Vormann, Marianne K.; Hutter, Simon; Lanz, Henriette; Wilmer, Martijn; Ramp, Daniela; Masereeuw, Rosalinde; Vriend, Jelle [in: The AAPS Journal]Drug-induced kidney injury is often observed in the clinics and can lead to long-term organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a three-channel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin). The effect on cell viability and NAG release into the medium was determined. A novel panel of four miRNAs (mir-21, mir-29a, mir-34a, and mir-192) was selected as potential biomarkers of proximal tubule damage. After nephrotoxicant treatment, miRNA levels in culture medium were earlier indicators than cell viability (WST-8 assay) and outperformed NAG for proximal tubule damage. In particular, mir-29a, mir-34a, and mir-192 were highly reproducible between experiments and across compounds, whereas mir-21 showed more variability. Moreover, similar data were obtained in two different laboratories, underlining the reproducibility and technical transferability of the results, a key requirement for the implementation of novel biomarkers. In conclusion, the selected miRNAs behaved like sensitive biomarkers of damage to tubular epithelial cells caused by several nephrotoxicity mechanisms. This biomarker panel, in combination with the 3D cultures of ciPTEC-OAT1 in the OrganoPlate, represents a novel tool for in vitro nephrotoxicity detection. These results pave the way for the application of miRNAs in longitudinal, time-course in vitro toxicity studies.01 - Zeitschriftenartikel, Journalartikel oder Magazin
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